Nystagmus comes from the Greek word “nystagmos”, which means to nod or drowsiness, and “nystazein” to doze. It is a rhythmic, involuntary oscillation of one or both eyes. Using the information obtained from a complete history, physical examination, and radiographic and eye movement recordings, over forty types of nystagmus can be distinguished. Some forms of nystagmus are physiologic, whereas others are pathologic.
Although nystagmus is typically described by its more easily observable fast (jerk) phase, the salient clinical and pathologic feature is the presence of a slow phase in one or both directions. Thus, clinical descriptions of nystagmus are usually based on the direction of the fast phase and are termed horizontal, vertical, torsional, or any combination of these. The nystagmus may be conjugate or dysconjugate. The nystagmus may be predominantly pendular or jerky, the former referring to equal velocity to-and-fro movement of the eyes, and the latter referring to the eyes moving faster in one direction and slower in the other. Involuntary ocular oscillations containing only fast phases are “saccadic oscillations and intrusions” and not nystagmus. It is well documented that these differences may be difficult, if not impossible, to differentiate clinically and can only be accomplished with eye movement recordings. Recent advances in eye movement recording technology have increased its application in infants and children who have clinical disturbances of the ocular motor system.
Infantile nystagmus syndrome (INS) is an ocular motor disorder of unknown etiology, which presents at birth or early infancy and is clinically characterized by involuntary oscillations of the eyes. INS is defined according to the National Eye Institute collaborative Classification of Eye Movement Abnormalities and Strabismus (CEMAS). Estimations of incidence of INS vary from 1 in 500 to 1 in 6,000. Clinical characteristics include: increased intensity with fixation and decreased with sleep or inattention; variable intensity in some position of gaze (a null position); changing direction in different positions of gaze (about a neutral position); decreased intensity (damping) with convergence; anomalous head posturing; strabismus; and the increased incidence of significant refractive errors. INS can occur in association with congenital or acquired defects in the visual sensory system (e.g., albinism, achromatopsia, and congenital cataracts).
Nystagmus can cause significant impairment in vision. Visual symptoms are very common and are inversely proportional to the frequency (and speed) of the oscillation in the eye. Visual sensitivity for both pattern and movement detection is reduced because of these eye movements. Images spend little time in the foveal area, and image movement, often in excess of 80 degrees/second causes blur, oscillopsia, diplopia, and vertigo. These symptoms begin at retinal slip velocities of greater than 4 degrees/second. Abolishing or reducing the nystagmus frequency ameliorates these symptoms.
Ideally, the treatment of nystagmus would be directed against the pathophysiological brain mechanism responsible for the ocular oscillation. Alternative secondary ameliorative therapies treat the eyes directly, and include prism glasses, contact lenses, occlusion of one eye, botulinum toxin, anesthetic injections, and eye muscle surgery.
INS and adult nystagmus may respond to drug treatment. Some patients benefit from gabapentin, scopolamine, clonazepam, or valproate. All of these drugs have limited usefulness due to a significant number of systemic side effects.
Multiple examples of level II and II based-medical evidence suggest that eye muscle surgery improves nystagmus and visual function in patients with INS or adult nystagmus. Variables reported pre- and post-operatively in patients with INS include: optotype and gaze dependent acuity, contrast sensitivity, motion detection, null zone characteristics, visual recognition time, subjective visual function and electrophysiological characteristics. Patients from multiple studies, who had their null zone optotype best-corrected binocular vision tested within 1 week and 4 to 6 weeks after eye muscle surgery (INS grouped mean data), showed a significant improvement. Overall, seventy-five percent improved 1-3 lines and fifteen percent improved 3 lines or greater.
Eye movement recordings also show that surgical intervention increases the prevalence of favorable nystagmus waveforms. However, even if the nystagmus is completely eliminated, the integrity of the afferent system (optic nerve, retina, brain disease) and the age-related timing of surgery limit the acuity potential in any one patient with INS.
As a result of eye muscle surgery improving their beat-to-beat nystagmus, patients receive more useful vision per unit time and as a function of gaze, recognize objects faster, have less head movement, better motion, and contrast sensitivity, thus “function” better. The common clinical perception is that eye muscle surgery only serves to centralize the INS null position. In fact, what happens is a broadening and deepening of the null zone. Data accumulated over the last 30 years shows that many afferent and efferent visual system measures improve as a result of eye muscle surgery on INS patients, regardless of the indication (eccentric null, vergence damping, strabismus or nystagmus alone), suggesting that neurovisual changes take place as a result of the surgical procedure itself, unrelated to moving or removing some of the extra ocular muscle. The current hypothesis is that surgical interference with peripheral extraocular muscle/tendon, “enthesial” proprioceptive nerve endings influence central ocular motor pathways, resulting in an improved INS oscillation.
Electrophysiological analysis using precise eye movement recordings have provided a new basis for eye movement abnormality classification, etiology, and treatment. These electrophysiological investigations have had a significant impact on eye movement systems research in much the same way as electrocardiography did on the study of cardiac rhythms. Eye movement recording methodology is most commonly used as a research tool by neurologists, neurophysiologists, psychophysicists, psychologists/psychiatrists, ophthalmologists, and optometrists. Practical applications of eye movement recording technology in clinical medicine include diagnosis/differentiation of eye movement disorders and utility as an “outcome measure” in clinical research. Eye movement recordings, by convention, display data during continuous periods of time. Position and velocity traces are clearly marked with up being rightward or upward eye movements and down being leftward or downward eye movements.
Multiple studies have used measures obtained from eye movement recordings to evaluate varied treatment effects on patients with nystagmus. For example, Kim et al., Jain et al., DePalo et al., Bandini et al., Stahl et al., Young et al., Leigh et al., and Hertle et al. all used frequency measures obtained from eye movement recordings to evaluate varied treatment effects on patients with nystagmus. In those studies where therapy decreased the patient's symptoms and signs, eye movement recordings showed an improvement in the nystagmus.
It has been discovered that certain pyrethroid compounds, when administered, intraocular, through topical administration or implantation of an ocular device or contact lens containing the pyrethroid, have a significant impact in improving nystagmus and the visual abnormalities associated therewith, without the attendant disadvantages of medication side effects or invasive surgery. The pyrethroid compounds are formulated in a topical ophthalmic delivery system, such as a solution, suspension, ointment or gel, or incorporated into an ocular device, such as an ocular implant, reservoir or contact lens.
Pyrethroids are a group of man-made (synthetic) pesticides designed to resemble the natural pesticide pyrethrum, which is produced by chrysanthemum flowers. Pyrethroids disrupt the normal functioning of the nervous system in an organism or animal, including human, by prolonging the deactivation of voltage-gated sodium channels, which results in prolonged excitation of nerve fibers.
Synthetic pyrethroids containing an alpha-cyano group (such as lambda-cyhalothrin, the active ingredient in Hot Shot® Home Insect Control (Spectrum Brands) and Warrior IIR crop protection pesticide (Syngenta)) are more potent in eliciting neurotoxic effects, in comparison to pyrethroids that do not contain an alpha-cyano group.
While synthetic pyrethroids have a higher level of selectivity and toxicity for the insect nervous system, local effects on human skin resulting in paresthesias can occur in association with overexposure. Paresthesias are considered a local effect resulting from cutaneous overexposure to certain synthetic pyrethroids, in contrast to an effect mediated through the central nervous system.
Even so, systemic toxicity is uncommon in humans, as the dermal absorption of these chemicals appears to be minimal. Most cases of systemic poisoning and central nervous system effects from synthetic pyrethroids have been reported in association with occupational overexposure or from intentional ingestion. Field studies of agricultural workers with cutaneous exposure to synthetic pyrethroids have reported that when paresthesias occur, the abnormal sensations usually develop several hours after the time of contact. The paresthesia has been described as ranging from a mild itch to a stinging sensation, with progression to numbness in some cases. These paresthesias can be exacerbated by direct exposure to sunlight and upon contact with water. The duration of symptoms varies, ranging from several hours to approximately 24 hours. In most cases, there are no physical abnormalities (such as erythema, edema, or vesiculation) observed in areas of affected skin.
In a study that investigated abnormalities in neurological signs and electrophysiological findings among individuals who had experienced paresthesias from contact exposure to synthetic pyrethroids, no significant differences were observed in comparison to unexposed (control) subjects. Experimental studies and anecdotal reports have suggested that topical Vitamin E (alpha-tocopherol) can reduce the effect of paresthesias through mechanisms that are not well understood.
The warning label for lambda cyhalothrin-containing insecticides states that it is potentially fatal if swallowed, and that it causes “moderate eye irritation.” If the product contacts the eyes, the label recommends immediate rinsing followed by seeking the advice of a poison control center or physician. When handling the product, it indicates that handlers must wear eye protection.
It is an object of the invention to provide an ophthalmic composition comprising a pyrethroid compound useful in the treatment of eye movement disorders characterized by unwanted eye movements, such as nystagmus.
It is a further object of the invention to provide a method for the treatment of nystagmus or other conditions involving unwanted eye movements, which provides for significant and prolonged reduction of unwanted eye movements with little or no toxic local or systemic side effects.
It is yet another object of the invention to provide for pharmaceutical compositions comprising an effective amount of a pyrethroid compound, which may be administered topically in the eye or incorporated into an ocular implant, including but not limited to a reservoir, matrix, contact lens or other solid implantable device.
Still other objects of the invention will be evident from the disclosure herein.